Chen Ziqing
The persistence of NK-cells is limited by various immunosuppressive factors within solid tumor microenvironments including prostaglandin E2 (PGE2). We sought to investigate if activation by the type I cytokines IL-2 and IL-15 differ in their ability to render NK-cells resistant to PGE2-mediated suppression. Cytokine-activated NK-cells were tested for their function and ability to infiltrate lung adenocarcinoma tumors in the presence of PGE2. Experimental finding was extended to the analysis of NK-cell infiltration in patients with lung adenocarcinoma and TCGA data analysis was performed to investigate differences in NK-cell gene expression in relation to Prostaglandin E Synthase (PTGES) expression. IL-15 enriched a subset of CD25+/CD54+ NK-cells compared with IL-2 (52.6% vs 10.4%), superior mTOR activity (p<0.05) and activity of the cAMP hydrolysing enzyme phosphodiesterase 4A (PDE4A). This distinct population of NK-cells shows improved ability to form cell clusters. When exposed to PGE2, The CD25+/ CD54+ population maintained ability to kill K562 targets (6 time higher, p<0.05) compared with CD25-/CD54-, and to infiltrate lung adenocarcinoma 3D spheroids. In a cohort of patients (n=10) with lung adenocarcinoma, the frequency of NK-cells (CD56+/CD3-) expressing CD54 is significantly higher in the central tumor compared with the invasive margin and normal tissue (p<0.01). Furthermore, PTGES affects the prognostic value of NK-cells where a high-NK cell gene signature is associated with sig nificantly improved overall survival in patients with high PTGES expression (p<0.05). Our data uncover functional mechanisms used by IL-15 treated NK cells to persist in tumors and overcome the PGE2-mediate immune suppression, and strategies to selectively expand CD25+/CD54+ NK cells for adoptive cell therapy should be considered.